OXAZOLONS  AND  THEIR  REACTIONS. 


RING  FORMATION  THROUGH  THE 
P-POSITION  OF  THE  BENZENE  RING. 

THE  ESTERS  OF  P- AMINO  BENZOIC  ACI1). 


WILMA  MCCABE  MARLOWE 


THESIS 


FOR  THE 


DEGREE  OF  BACHELOR  OF  SCIENCE 


CHEMISTRY 


COLLEGE  OF  LIBERAL  ARTS  AND  SCIENCES 


UNIVERSITY  OF  ILLINOIS 


1921 


Digitized  by  the  Internet  Archive 
in  2015 


https://archive.org/details/oxazolonstheirreOOmarl 


UNIVERSITY  OF  ILLINOIS 


.%y„.2.7, i$l 


THIS  IS  TO  CERTIFY  THAT  THE  THESIS  PREPARED  UNDER  MY  SUPERVISION  BY 

WILMA  MC  CABE  MARLOWE 


ENTlTLED..QMS.QfcM§...Mi?...ll^IR...mcII.Qia*....,.jRINO...i,.QRMAT,IOIT...IHRO.U.GH.. 

.THE . . ,P.“P.0.S.  H I Oil. . . .QE. . . THE . . BENZENE . . li  ING .» THE. . .E  S TEES. . . QE . . B.rrAMl  N 0 

BENZOIC  ACID, 

IS  APPROVED  BY  ME  AS  FULFILLING  THIS  PART  OF  THE  REQUIREMENTS  FOR  THE 
degree  OF .....Bachelor.,  of. . . S c i en q g . . i.h. . . .C'/mmi.S/fcrY. 


Approved  : 


UT  \: 


HEAD  OF  DEPARTMENT  OF. 


CL 


i- 


sd 

i 

E-i 

f—i 

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' \ ' 

PAHT_3. 

I.  Introduction: 

Method  of  Preparation 
Purpose  of  Work 

1 

II.  Historical: 

2 

Methods  Used  in  Preparation'  of  Oxazolons 

and  Pentaoxaxolons 

III.  Theoretical: 

Chemistry  Composition  of 

C ompounds 

3 

IV.  Experimental  Work: 

Processes  carried  out  in 

Laboratory. 

6 

V.  Conclusion: 

10 

VI.  Bibliography. 

12 

PART  II. 

I.  Introduction. 

13 

II.  Historical 

13 

III.  Theoretical 

14 

IV.  Experimental 

16 

V.  Conclusions 

17 

VI.  Bibliography 

18 

' 

C 0 IT  T E IT  T S 


PIET  III. 


1.  Introduction:  19 

Commercial  Esters  of  p-Amino  Benzoic  Acid. 

Uses  of  Esters . 

Purpose  of  Work. 

II,  Historical:  20 

General  Anaesthetic's, 
local  Anaetliest ics  . 

Esters  of  Para  Amino  Benzoic  Acid. 

III.  Theoretical.  23 

Chemical  Constitution  and  Anaesthetic'  Effects. 
Effects  of  Side  Chains, 

IT.  Experimental.  25 

Preparation  of  llec'essary  Eeagehts, 

Preparation  of  Esters, 

V.  Conclusions.  29 

VI.  Bibliography.  20 

VII,  Acknowledgment,  32 


1 


OXAZOIONS THE  IP,  EE  ACT  I GITS. 

IITTRODUCTIj.it 

Oxazclons  were  studied  "by  carrying  cut  different  reactions 
in  order  to  determine  the  most  favorable  conditions  for  their  for- 
mation  and  their  hydrolysis  to  the  amino  alcohols. 

Oxazolons  may  be  prepared  by  condensing  (3  ohloroethyl 
chlorcarbonate  with  a primary  amine  and  refluxing  the  derivative 
of  c'arbam  in  ic  acid  with  an  aqueous  solution  of  sodium  hydroxide. 

2 RITH2  +-  C1C00CH2CH2C1  — ^R1TH-C0-CCH2CH2-C1 -f  RNH2*HC1 

NaOH  RNH-C0-0CH2CH2-C1  ~>RHH»C0-0  , -y-  NaCI  + H20 

\ \ 

ch2—  ch2 

If  an  excess  of  .sodium  hydroxide  is  sued  with  a longer 
period  of  refluxing  the  hydrolysis  takes  place  giving  the  amino 
alcohol . 

R1TH-C0-0  2UaOE  RNH-0H2-CH2-0H  Na2C03 

CH2  ch2 

P«nUxazolon»  have  bean  prepared  in  a similar  manner  us- 
ing the  prophyl  derivative  instead  of  the  ethyl  derivative.  These, 
too,  were  hydrolyzed  if  refluxed  with  an  excess  of  the  sodium  hy- 
droxide for  a long  time. 

It  was  thought  from  the  preparation  of  the  oxazolons 
and  the  pontaxazolons  that  the  nature  of  the  ring  might  be  varied 
by  using  different  chlorine  compounds  then  proceeding  in  a similar 
manner . 


2 


The  amino  alcohol  was  used  as  the  working  "basis  for  the 
preparation  of  endphenyl  ke  tomorjiholine , it  was  refluxed  with 
oxalyl  chloride  and  with  chloracetyl  chloride  to  form  the  keto 
morpholine  rings. 

0 ?« 

RNH-CH2CH0OH -f-Clcf -C~ °1  RN  — CH2CE2  -f  2HC1  . 

\ JO 


c — C ' 

* If 

0 0 


RNH-CH2CH20H  C1-CE2C-C1  ->>  RF^*-CH2CH2x-f  2HC1 


C-CH. 


HISTORICAL . 

Hernirowshy  prepared  A chlorethyl  chi 0 r ocarb  onat  e from 
phosgene  and  ethylene  chlorhydfiin.  He  condensed  this  @ chlorethyl 
chi or carbonate  with  aniline  and  with  ammonia  and  ieceived  the  cor- 
responding esters  of  the  c'arbaminic  acid.  The  n-phenyl  carbaminic 
chloroethyl  ester  gave  n-phenyl  oxazolon  when  refluxed  with  con- 
centrated potassium  hydroxide, 

Paul  Otto  in  following  up  the  work  of  Nemirowsky  prepared 
hydroyetyl  aniline  in  two  ways:  first  by  refluxing  the  phenyl  car- 
baminic  chloroethyl  ester  with  concentrated  potassium  hydroxide, 
also,  by  refluxing  ethylene  chlorohydrin  with  aniline.  Hydroxyethyi 
aniline  when  treated  with  liquid  x^Hosgene  in  a sealed  tube  gave 
n-phenyl  oxazolon.  He  formed  the  corresponding  carbominic  oster^, 
oxazolons,  and  amino  alcohols  from  methoxy  aniline  and  the 
and  naphthalenes  in  a similar  way. 


3 


J.  B.  Segur  used  the  methods  of  ITemir owsky  and  prepared 
a series  of  oxazolons  and  pentoxazolons . By  using  aromatic  amines 
as  aniline  and  substituted  aniline  as  the  substituent  groups  and 
by  condensing  these  with  ^3  clloroethyl  chlorcarbonate  he  pre- 
pared the  c’arbarninic  esters  which  were  refluxed  with  an  aqueous 
solution  of  sodium  hydroxide  to  give  the  oxazalons.  If  he  wished 
to  prepare  the  amino  alcohols  he  used  an  excess  of  the  alkali  in 
a concentrated  solution  which  favored  complete  hydrolysis.  The 
substituted  anilines  caused  a slower  reaction  than  the  simple 
ring  but  the  nature  and  position  of  the  group  did  not  affect  the 
reaction.  He  also  prepared  n-phenyloxazolon  by  condensing  hy 
droxyethyl  aniline  and  phosgene.  The  n-phenyl  oxazolon  would  not 
react  with  aniline  when  they  were  refluxed  together. 

He  prepared  the  pentoxazolons  in  an  analogous  manner, 
preparing  first  the  carbarn  in  ic'  esters  by  condensing  a primary 
aromatic  amine  with  if  chloroprophyl  chlorcarbonate  then  reflux- 
ing with  the  aqueous  solution  of  sodium  hydroxide.  He  formed  the 
hydroxy  prophyl  amines  by  using  an  excess  of  alkali  in  a concen- 
trated solution. 

This  method  proved  more  satisfactory  and  gave  better 
yields  than  by  using  ethylene  c’hlorhydrin  and  the  aromatic  amine 
to  give  the  hydroxy  amines. 


THEORETICAL 


It  has  been  proved  that  oxazolons  may  be  prepared  by 


- 

* 


, 


•;  . 


4 


using;  & substance  with  active  chlorine  and  a primary  aromatic  amine 
to  give  the  carbarn  in  ic'  ester  which  is  hydrolyzed  with  an  aqueous 
solution  of  sodium  hydroxide. 

2 RNHgf  C1C00CH2CH2C1  — RN  B-CO-OCHgCHg-Cl-A  RNHg*  HCL 


NaOH 


-f-  RNH-C0-0CH2CH2-Cl  — > RN  -C0-0^  -f-  NaCl+HgO 

ch2-  ch2 


These  reactions  take  place  very  readily  using  aniline  or  some 
amine  with  substitutions  in  the  ring  as  c’hl or,  methyl,  ethyl, 
methoxy,  or  ethoxy  groups  in  the  ortho  or  para  positions.  These 
substituting  groups  have  no  effect  on  the  reaction  except  to 
make  it  slower,,  therefore  a longer  period  of  refluxing  . One  mole 
of  carbominic  acid  when  refluxed  with  one  mole  of  sodium  hydroxide 
in  an  aqueous  solution  loses  ono  mole  of  hydrochloric  acid  and  forms 
one  mole  of  the  oxazolon.  The  best  conditions  for  this  reaction 
are  one  mole  of  alkali  in  a 25$  solution  for  one  mole  of  ester. 

If  the  sodium  hydroxide  is  more  concentrated  it  tends  to  shift 
the  reaction  toward  a more  complete  hydrolysis.  Eftt  if  the  time 
of  refluxing  and  the  concentration  are  carefully  controlled  very 
little  of  the  ester  is  hydrolyzed.  By  using  a more  concentrated 
solution,  33$,  and  five  moles  of  the  alkali  for  one  mole  of  the 
ester  a complete  hydrolysis  takes  place  giving  a good  yield  of 
the  amino  alcohol. 


5 


The  amino  alcohol  may  also  he  prepared  by  cdndensing 
a mole  of  a primary  aromatic  amine  with  one  mole  of  ethylene 
c’hl orhydr in . This  method  however  gives  much  smaller  yields, 
therefore,  it  is  better  to  use  the  hydrolysis  method. 

In  most  casoc  the  reactions  will  take  place  when  re- 
fluxed for  two  hours,  hut  if  a substituted  phenyl  group  is  used 
the  time  of  refluxing  must  necessarily  ho  prolonged  to  about 
four  hours. 


Oxazolon  may  also  be  prepared  by  using  one  mole  of 
phosgene  and  one  mole  of  the  amino  alcohol  together  in  a ben- 
zene solution.  This ,howe ver , involved  more  reactions  than  the 
former  way  of  preparation. 

The  pentaoxazolons  have  been  prepared  in  the  same  way 
as  the  oxazolons.  The  c'arbaminic  ester  is  first  formed 

2MTH2+  ClC0-0-CH2CH2CH2Cl >>  RI!H-C0-0CH2CH2CH2C1-+-  B1TH2. HCL 


then  the  propyl  chlorester  is  refluxed  in  an  aqueous  solution 
of  sodium  hydroxide. 


ENH-C0-0CH2CH2CH2C1  -f-NaOH  — *Rlf  -CO-O^ 


\ 


CH* 


-f  !TaCl+H20 


The  propyl  hydroxy  amine  is  formed  if  a concentrated 
alkali  solution  is  used  in  excess  as  in  the  case  of  the  ethyl 
hydroxy  amine.  The  strength  and  the  amount  of  alkali  ha-"e  the 
same  effec.t  on  the  pent  oxazolons  and  amino  alchols  as  on  the 
oxazolons . 


The  substituted  groups  in  the  phenyl  ring  may  also  bo 

fe 


6 


■used  to  prepare  the  pnet oxazolons  as  well  as  the  oxazolons.  Again 
it  takes  a longer  period  of  refluxing  for  the  reaction  to  go  to 
completion. 


Reduction  with  absolute  alcohol  and  sodium  was  tried  as 
a different  method  for  preparing  the  amino  alcohol  hut  the  yield 
was  so  small  that  it  seemed  impractical  as  a method  of  preparation. 

The  manner  of  preparing  the  keto  morphalines  may  he  some 
what  similar,  to  the  method  of  preparing  the  oxazolons  and  the 
pentoxazolons . As  a basis  for  this  work  the  hydroxy  ethyl  amine 
was  used  as  the  unit. 

The  reaction  with  cxalyl  chloride  was  tried 

0 0 


rhh*ch2ch2oh  + Clff-6-Cl 


RF  — CH2CH2 
V /Q 

o ~r 


-f  2HC1. 


Equal  molecular  weights  v;ere  refluxed  for  four  hours.  The  reac- 
tion was  carried  out  in  a solution  of  benzene.  At  first  the  reac- 
tion eas  a little  violent  with  considerable  heating  effect  but 
this  did  not  continue  long,  The  reaction  mixture  was  then  re- 
fluxed with  an  open  flame  for  four  hours.  The  compound  on  cool- 
ing was  a thick,  sticky,  white  mass. 

A reaction  with  c'hlorac'e tyl  chloride  was  also  tried. 

It  was  carried  out  in  the  dame  way  as  the  oxalyl  reaction.  The 
edmpound  formed  was  a viscous  liquid  of  a yellowish  brown  color. 


Using  the  methods  and  proportions  as  given  by  Hr.  Segur 


7 


'in  his  thesis  for  'taster  of  Science  the  different  steps  of  the 
preparation  wore  carried  out.  First  thing  done  was  the  purifica- 
tion of  the  product  as  prepared  "by  Mr.  Segur.  This  gave  some  idea 
of  the  physical  properties  of  the  compound  and  also  a method  of 
purification.  It  was  recrystallized  from  hot  ethyl  alcohol.  Then 
successive  steps  of  the  procedure  were  tried.  The  first  step  of 
preparing  the  chi  or  ethylc'hlorcarbonate  was  not  carried  out. 


was  dissolved  in  "benzene  then  the  two  "benzene  solutions  were  slow- 
ly mixed.  The  hydrochloride  of  aniline  precipitated  from  the  "ben- 
zene solution;  therefore  it  was  necessary  to  use  sufficient  quan- 
tity of  "benzene  to  keep  the  mixture  thin  enough  to  he  stirred  eas- 
ily. The  aniline  hydrochloride  was  filtered  off  and  the  filtrate 
containing  the  product  was  washed,  with  dilute  hydrochloric  acid 
then  with  water  to  remove  all  the  aniline  and  aniline  hydrochloride. 
The  "benzene  was  distilled  off  and  the  product  crystallized  when  it 
Cooled.  The  product  was  recrystallized  from  hot  alcohol.  This 
procedure  was  repeated  several  times  getijng  a yield  of  about  8 Q^, 


I . PEEP  AD. STEF.  OF  SUBSTI- 

TUTED CAEBOHIITIC  acid 


For  this  reaction  two  moles  o 


the  aniline  were  used  for 


each,  mole  of  the 


chlorethyl  chloscarhonate . Each  substance 


6 2.3  gr  s . 


Cl  Clio  CHoCOO  Cl 


48  grs 


II.  PREPARATION  OF  THE  QXAZ0L02T  AZTD  THE 
All  I HO  ALCOHOL 


e 


Hols  per  mole  of  carbaminic  ester  for  alkali  were  re- 
flexed  together  for  two  hours.  The  alkali  was  made  into  a twenty 
five  per  cent  aqueous  solution.  This  seamed  to  he  the  “best  condi- 
tions for  the  preparation  of  the  oxazolon.  The  yields  were  round 
70  per  cent. 

Carbaminic  ester  20  gra„ 

Sodium  Hydroxide  4 grs. 

N-phenyl  Oxazolon  10.9  grs. 

70 yield 

Preparation  of  Amino  Alcohol,  by  B eductions. 

Twenty  grains  of  the  oxazolon  was  dissolved  in  fifty 
cubic  centimeters  of  ethyl  alcohol.  Twelve  grams  of  sodium  were 
cut  into  small  cubes  placed  in  a round  bottom  flask  and  covered 
with  toluene.  The  toluene  was  heated  until  the  sodium  melted. 

The  mixture  was  stirred  with  a mercury  sealed  mechanical  stirrer 
run  by  a motor.  The  alcoholic'  solution  of  the  oxazolon  was  drop- 
ped onto  the  sodium  mixture  slowly  by  means  of  a separatory  funnel. 
The  solution  was  kept  hot,  no  heat  was  applied  to  the  flask  after 
the  initial  melting.  This  mixture  was  stirred  for  two  and  one- 
half  hours.  Water  was  then  added  slowly  to  decompose  the  unused 

sodium.  The  contents  of  the  flask  were  steam  distilled  and  three 

have 

fractions  collected.  The  one  thought  tc/contained  the  reduced  pro- 
duct was  washed  with  ether  and  distilled.  Three  fractions  were 

•>  ■ » . i. 

collected  but  the  yield  of  yellow  oil  was  extremely  low.  There- 
fore this  method  seemed  impractical  as  a means  of  preparing  the 
alcohol . 

The  Preparation  of  the  Amino  Alcohol 
by  Hydrolysis . 


9 


The  carhominic'  eater  was  hydrolyzed  hy  using  a large 
excess  of  alkali  in  a water  solution.  Pive  moles  of  alkali  were 
used  for  one  moo  of  the  carhominic"  ester.  Using  these  proportions 
yields  of  85g--SQ^  of  alcohol  were  prepared. 

It  was  attempted  to  prepare  the  phenylisocyanate  deri- 
vative of  the  alcohol.  Hole  per  mole  was  used  and  the  solid 
which  was  formed  was  diphenylurea  in  an  impure  state. 

1 1 1 PREPARATION  OP  THE  KETO  HOEPHOLIITES 

Endphenyl  koto  morpholine 

The  amino  "alcohol  was  dissolved  in  "benzene  also  the 
oxalyl  chloride  then  the  two  "benzene  solutions  added  together  ana 
refluxed  for  four  hours.  At  first  the  reaction  was  a little  active 
"but  this  heating  effect  did  not  last  long.  It  then  refluxed  quiet- 
ly. The  derivative  separated  out  as  a thick,  sticky  mass.  At  first 
it  would  not  crystallize  from  any  of  the  common  organic"  solvents; 
hut  after  it  had  stood  for  several  weks  it  seemed  grandular  in  ap- 
pearance and  crystallized  easily  from  alcohol.  Yielding  a white 
crystalline  solid  with  a melting  point  of  158°  with  a yield  of 
80 of  the  crude  product. 


Hydroxy  ethyl  aniline 

5 

.33  grs. 

Oxalyl  chloride 

5 

6 r s . 

Endphenyl  keto  morpholine 

S 

grs  crude 

80  $ yield. 


10 


Endr henyl  di  he  to  morpholine 

The  hydr oxyathyl  aniline  and  chi or ace tyl  chloride  we re 
4ach  dissolved  in  “benzene,  then  the  two  solutions  slowly  added  to- 
gether and  refluxed  for  four  hours.  The  diketomorpholine  sepa- 
rating out  as  a thick  “brown  syrupy  substance.  The  “benzene  was 
distilled  off  then  the  dikoto  morpholine  distilled  under  dimin- 
ished pressure.  33. P,  215°  - 220°  with  15  mm  pressure  yielding 
69  fo. 

Hydroxyl thyl  aniline  12  grs. 

Chloracetyl  chloride  10  grs 

Endphenyl  diketo  morpholine  12.  grs. 

69  ^ 


CONCLUSIONS. 

The  oxazolons  and  pentoxazolons  may  “be  prepared  “by  using 
the  chlorethyl  chlorcarbonate  with  aniline  then  refluxing  the 

ester  of  c'arbaminic  acid  with  a 25  fo  solution  of  Na  OE  for  two 
hours . 

If  the  amino  alcohol  is  desired  an  excess  of  1:  5 moles 
of  NaOH  is  uded  in  order  to  completly  hydrolyze  the  carbaminic 
ester . 

The  ring  may  be  altered  by  using  different  reagents  as 
chloracetyl , chloride  or  oxalyl  chloride  to  form  the  keto  morpha- 
lines.  These  substances  require  a longer  period  of  refluxing  and 
use  the  hydroxy  ethyl  aniline  as  the  reacting  substance. 


11 


Theoretical  amounts 
were  each  dissolved 
of  the  amino  alcohol 


of  chloracttyl  chloride  and  oxalyl  chloride 
in  benzene  then  added  to  throoretical  amounts 
and  refluzed  for  four  hours  with  a low  flame. 


. 


■ 


B I B L I 0 G R A PHY 


PART  I 


J ourn . 

of 

Pract.  Chemie 

(2). 

31; 

173-175 

Journ* 

of 

Pract.  Chemie 

(2) 

44; 

15-  23 

3,  The  Formation  of  Oxazolons  and  Pentoxazolons  and 
Their  Hydrolysis  to  Amino  Alcohols* 


Thesi3  for  the  Degree  of  Master  of  Science  at  the 
University  of  Illinois--1920« 


13 


RING  FORMATION  THROUGH  THE  PARA 
POSITION  OF  THE  BENZENE  RING 


INTRO  D UCTI  0 N 


Ring  formation  through  the  meta  position  of  the  ben- 
zene ring  has  been  prepared  by  Julius  V.  Braun  , L.  Karpf  and 
W.  v Garn  by  using  a meta  compound.  Using  a para  compound  in- 
stead  of  a meta  compound  the  formation  of  the  ring  would  take 
place  in  this  position  instead  of  the  meta  position.  It  was 
the  purpose  of  this  work  to  prepare  a ring  compound  through 
the  para  position  using  a very  similar  method  of  preparation 
to  that  used  by  Braun,  Karpf  and  Garn. 

HISTORICAL 

In  the  preparation  of  the  ring  formation  meta 
xylene  was  used,  this  was  brominated  by  slowly  adding  four 
moles  of  bromine;  the  bromide  was  fractionated  at  fifteen 
milimeters  of  pressure,  then  pressed  with  150-200  atmospheres 
for  twenty-four  hours  to  remove  the  oil.  The  powdered  bromide 
was  added  to  a 10$  excess  alcoholic  solution  of  potassium  cya- 
nide and  heated  for  2-  3 hours  on  the  steam  bath  yielding  from 
45  tO  55 $ of  the  cyanide.  One  mole  of  this  cyanide  in  a near- 
ly boiling  solution  of  absolute  alcohol  was  poured  on  sixteen 
atoms  of  sodium  giving  a 35  to  40 $ yield  of  basic  compound. 
This  was  fractionated  giving  two  fractions  A a mono  amino 


i.  - 


. 


, 


. 


- 


• ■ i 


* 


14 


B.  P.  97°-  98°  and  B Ui  (J  diamino  m-diethyl  benzene  B.P. 
160°-170°. 


The  product  A is  a secondary  amine  and  when  attached  to 
a hezene  ring  probably  takes  this  form  -- 

i.  3,  c6h4 


CH~ 

o 

/ 


CH«  — CHp v 

\ /NH  or  1,3  C6H4-CHx 

nch2-ch2  / nh 

2 2 ch2-  ch/ 


less  probably  -- 


CHr 


1,  3 C6H4-CH 


\ " NH 

XCH  / 

CH3 


THEORETICAL 


The  ring  formation  in  the  para  position  might  be 
formed  in  a somewhat  similar  fashion.  The  side  chain  would 
have  to  be  sufficiently  long  to  maintain  the  ring  formation 
and  keep  the  proper  spaces  between  the  carbon  atoms. 

Starting  with  a sodium  salt  a para  nitro  phenol  and 
condensing  this  with  trimethylene  bromide  to  form  the  brcm  ether. 

1,  N02  (4)'  ONa  C6  H4  4.  BrCH2CE2CH2Br  

1,4,  N02  C6H4  0CH2CH2CH2Br  j.  NaBr 
Treat  the  bromine  compound  as  in  the  meta  ring  compound  with  an 


t ■€ 


' 


r 


\ 

I 


15 


alcoholic  solution  of  potassium  cyanide  forming  the  cyanide* 

1,  4,  C6  H4  N02  0CH2CH2CE2Br  + KCN 

1,  4,  c6  H4  N02  0CH2CH2CH2CN  f KBr, 

Then  hy  reduction  with  stannous  chloride  and  hydro- 
chloric acid  reduce  the  nitro  group  to  an  amino  group*  Further 
reduction  in  an  alkaline  solution  affecting  the  cyanide  group 
would  close  the  side  chain  with  the  amino  group  and  make  a 
ring  through  the  para  position  as 


1,  4,  C6  H4  N02  0CH2CH2CH2CN  -IS.1 ■ > 1,4,  C6H4  NH2  0CH2CH2CH2CN 

SnCl2 

SnCl4  -f  2H20. 


1,4,  C6E4  NH2  0CH2CH2CH2CN  CgE4-0 -CH2- CH2  ^ 


\ 


NH-CH 


/Ch2 


It  would  probably  be  better  to  reduce  the  nitro 
group  before  putting  on  the  cyanide  group,  as  it  would  be 
difficult  to  carry  out  both  reductions  without  destroying 


one  group. 


r 


■ 


! 


• * 


i 


■ 


16 


EXPERIMENTAL 

The  sodium  salt  of  para  nitro  phenol  was  prepared  by 
using  molecular  weights  of  little  p-nitro  phenol  and  sodium 
hydroxide  in  enough  water  to  dissolve  the  sodium  hydroxide. 

The  sodium  salt  was  crys tallized,  filtered  and  dried;  then  one 
mole  of  this  sodium  salt  was  refluxed  for  two  days  with  one  and 
one-half  moles  of  tr imethylene  hromide  in  about  six  hundred  cen- 
timeters of  water.  Most  of  the  color  left  the  aqueous  layer  and 
went  into  the  trimethylene  bromide  layer  making  it  a very  dark 
brown.  This  product  was  steam  distilled  to  remove  the  excess 
trimethylene  bromide  then  the  heavy  dark  brown  oily  product  was 
vacuum  distilled  using  a pressure  of  2 mm.  At  first  the  product 
could  not  be  distilled  because  a low  enough  pressure  could  not  be 
obtained,  but  after  getting  a pressure  of  2 mm  it  distilled.  It 
was  tried  to  crystallize  the  product  from  the  oil  by  means  of  a 
freezing  solution  of  hydrochloric  acid  and  ice  but  no  solid  would 
separate  out.  The  only  way  to  obtain  a solid  was  by  vacuum  dis- 
tillation. 

Reduction  was  tried  on  the  brown  oil,  but  it  would  not 
go  into  solution.  However,  after  vacuum  distillation  the  crystals 
were  put  into  the  reducing  mixture  of  hydrochloric  acid  and  stan- 
nous chloride,  but  no  reduction  took  place.  The  same  product 
came  out  through  all  the  processes--  para  nitro  phenol. 


Another  run  was  made  using  three  moles  of  triraethylene 


.1 


. a 


r 


. . . : . 


• « 


■ - 


* 


•• 


%J  ■ ■ n. 


r 


, 


• • ' • • ' ..  • .1  t . ■. 


1 


> : , 


. 


17 


bromide  Instead  of  one  and  one»llalf  moles  to  one  mole  of  the 
sodium  salt  of  para  nitro  phenol  but  this  did  not  work  any  bet- 
ter. 

An  attempt  was  made  to  nitrate  the  phenol  brom  propyl 
ether  using  fuming  nitric  acid  at  room  temperature  but  this  was 
not  successful.  No  other  methods  of  nitration  were  tried. 

CONCLUSION 

The  ring  compound  could  not  be  formed  by  this  method 
unless  the  para  nitro  brom  ether  could  be  prepared.  All  the 
way  through  the  process  a heavy  brownish  green  oil  adhered  to 
the  para  nitro  phenol,  this  may  be  what  interf erred  frith  the 
reaction  and  even  after  re-crystallization  with  ether  and 
petroleum  ether  the  oil  adhered  to  the  crystals. 


- v ~ ■ v l , \ i. . 

• , - : ..  . , 


BIBLIOGRAPHY 


Part  II 


1. 

Bar.  1881 

14 

2636 

2. 

Am.  Chem.  Jour. 

1 

271 

3. 

Ann.  Ch.  Phys . 

3 

27,461 

4. 

Ber . 

14. 

899 

5. 

Bar . 

16 

2715 

6 . 

Ber. 

15 

1002 

7. 

Ber . 

53  B 

98-109  (1920) 

8. 

Chem.  Abstracts 

11 

2492 

19 


ESTERS OF  PARA- AMINO  BENZOIC  ACID 

INTRODUCTION . 

From  the  work  on  anaesthetics  it  has  been  found 
that  the  esters  of  para-amino  "benzoic  acid  have  a decided 
anaesthetic  power  varying  in  intensity  with  the  different 
members.  Some  of  the  esters  as  methyl  ester,  "Orthaf or in u , 
ethyl  ester,  "Anaesthesin , prophyl  esters  "Propaesin"  and 
isobutyl  ester,  "Cycloforln*',  have  been  prepared  as  commer- 
cial products  of  q.uite  general  use,  the  most  common  being 
the  ethyl  ester. 

It  was  the  purpose  of  this  work  to  continue  in 
the  preparation  of  other  alliphatic  esters  of  para  amino 
benzoic  acid.  From  a comparison  of  the  physical  and 
chemical  properties  of  these  esters  it  was  hoped  some  con- 
clusions might  be  drawn  as  the  cause  of  the  anaesthetic 
properties  of  the  different  esters.  It  was  thought  that 
the  anaesthetic  powers  of  the  esters  might  be  a function 
of  the  surface  tension  and  the  partition  coefficient  and 
these  were  to  be  carefully  determined. 


20 


HISTORICAL 

For  many  ages  the  people  of  the  Orient  have  used 
sleep  producing  substances  as  opium,  Indian  Hemp,  and  other 
herbs;  with  the  advance  of  science  anaesthetics  and  other 
saporifica  have  been  synthesized  and  used.  As  early  as 
1799  Sir  Humphrey  Davy  discovered  the  anaesthetic  power  of 
nitrous  oxide,  Dr.  W.  C.  Long  found  that  ether  had  anaesthe- 
tic power  in  1842,  while  a short  time  later  in  1847  Prof. 

Simpson  introduced  chloroform  as  an  anaesthetic. 

5 

Dr.  H,  M.  Biggs  made  a very  extensive  study  of  local 
anaesthetics  and  tested  the  properties  of  cocaine  which  has 
been  the  most  widely  used  local  anaesthetic.  A good  deal  of 
work  has  been  done  in  organic  chemistry  to  find  some  synthetic 
compound  which  might  replace  the  cocaine  as  a local  anaesthetic. 

The  esters  of  para  amino  benzoic  acid  have  been  rather 
widely  studied  in  order  to  obtain  their  relative  anaesthetic 
power.  Patents  in  Germany,  Great  Britian,  and  the  United 
States  have  been  taken  out  for  several  of  these  esters.  The 
most  important  paper  on  the  relative  value  of  these  esters  is 

n 13 

by  Stunners  and  Luders.  They  made  a comparative  study  of 
the  solubilities  and  anaesthetic  properties  of  the  methyl  ethyl 
normal  propyl,  isoprophyl  and  isobutyl  esters  concluding  that 
the  normal  prophyl  ester  was  most  satisfactory  as  it  comes 


21 


midway  in  the  aeries.  The  anaesthetic  power  seems  to  increase 

with  the  size  of  the  esterifying  group,  hut  the  esters  become 

more  insoluble  as  the  group  increases  in  we ight ; therefor e those 

esters  in  the  mean  portion  of  the  series  are  most  satisfactory. 

21 

Mr.  Westermann  in  further  work  concluded  that  the  normal  amyl 

ester  had  the  strongest  anaesthetic  power  with  the  mildest  ef- 

fects  of  those  which  he  studied. 

4 

Beilstein  gives  the  method  of  preparation  and  properties 

8 

of  the  methyl  ester  as  prepared  by  Einhorn  and  Oppenlioimer. 

12 

Salowski  prepared  the  ethyl  ester  by  passing  hydrochloric 
acid  gas  through  a solution  of  p-amino  benzoic  acid  in  ethyl  al« 
cohol,  the  hydrochloride  thus  formed  was  decomposed  by  neutral- 
ising with  soda  solution  giving  the  free  amino  ester.  Limpricht 
10 

and  Sarr  esterfied  the  p-nitro  benzoic  acid  then  reduced  the 

nitro  ester  with  ammonium  sulfide  to  the  amino  ester.  Torlander 
14 

and  Meyer  also  give  a method  of  preparation. 

15  16,17 

The  normal  prophyl  and  iso  prophyl  esters  are  described 
in  patents  of  Germany  and  Great  Britain,  These  esters  are  prepar- 
ed in  the  same  way  as  the  ethyl  ester. 

18 

The  isobutyl  ester  is  covered  by  a patent  in  which  several 
methods  of  preparation  are  given:  by  direct  esterf icat ion  of  the 

para  amino  benzoic  acid  with  isobutyl  alcohol  and  passing  in  dry 
hydrochloric  acid  gas;  by  direct  esterf icat ion  of  the  para  nitro 
benzoic  acid  with  isobutyl  alcohol  and  reduction  with  stannous 


22. 


chloride;  "by  esterification  of  benzoic  azo  beta  napihol  with 
isobutyl  alcohol  and  reduction  with  bromide  of  the  alcohol  as 
the  esterifying  unit. 

21 

Mr.  Richard  Wilbur  Westermann  in  his  thesis  on 
"Various  Esters  of  Para  Amino  Benzoic  Acid"  gives  methods 
of  preparing  the  methyl  ethyl  normal  prophyl  isopropyl,  is- 
obutyl normal  amyl , and  isoamyl  esters.  He  found  the  method 
of  direct  esterification  of  the  alcohol  and  the  p-nitro  benzoic 
acid,  with  a little  hydrochloric  or  a little  sulphuric  acid  as 
catalyt  then  reduction  the  best  for  the  alcohols  of  low  molecu- 
lar weight.  While  those  of  higher  molecular  weight  the  p-nitro 
benzoyl  chloride  is  used  instead  of  the  acid  and  alcohol  is 
used  as  solvent  in  the  reduction  using  powdered  iron  and  hy- 
drochloric acid  to  reduce  the  nitro  esters. 


23 


THEORETICAL 

All  aromatic  compounds  have  some  anaesthetic  power* 

3 

Speigel  in  his  book,  "Chemical  Constitution  and  Physiological 
Action"  presents  many  interesting  ideas  and  conclusions  on  the 
subject  of  anaesthetics.  It  has  been  found  that  certain  nucleii 
have  a given  physiological  action,  this  action  may  be  weakened 
or  strengthened  by  introduction  of  side  chains  on  the  nucleii. 
Different  groups  hare  different  effects;  some  groups  bring  out 
the  properties  of  the  nucleus  while  others  counteract  its  effects* 

The  effects  of  the  amino,  hydroxyl,  and  carboxyl 
groppe  are  very  striking  and  are  often  times  strong  enough  to 
make  it  necessary  to  introduce  another  group  into  the  ring  to 
make  the  compound  reliable  for  therapeutic  purposes.  The  amino 
compounds  may  be  weakened  by  introducing  an  acid  constituent 
which  neutralizes  the  basic  effect  of  the  amine,  care  must  be 
taken  that  all  the  power  is  not  removed  by  the  neutralizing 
group. 

The  effect  of  the  side  chains  is  often  altered  by 
changing  the  length  of  the  chain.  In  the  study  of  para  amino 
benzoic  esters  it  has  been  found  that  the  anaethetic  power 
increases  withthe  length  of  the  chain,  sometimes  the  action 
becomes  stringent  and  it  is  not  pleasant  to  use,  but  this  can 
be  controlled  by  the  substituting  gropps* 


X 

. 


. . 


: 

. 


, t 


* 


% ' ..... 


, 


, 


v‘  - 


24 


Nearly  all  amino  hydroxy  esters  of  benzoic  acid 
have  local  anaesthetic  powers,  it  was  found  by  experiment 
that  the  hydroxy  group  was  not  neaessary  that  the  esters 
of  para  amino  benzoic  acid  have  the  same  anaesthetic  power 
and  are  more  soluble  therefore  more  usable  in  anaesthetic 
work*  The  less  soluble  esters  may  be  used  in  external 
work*  Where  they  may  be  dusted  on  to  affect  the  nerve 

ends,  but  little  use  can  be  made  if  they  have  to  be  injected. 
The  hydrochlorides  of  the  amines  are  soluble  but  are  too 
stringent  to  be  used*  Therefore,  study  must  be  made  to  find 
esters  that  are  soluble  having  a strong  anaesthetic  action, 
but  not  astringent  action. 


i 


• 

* 

< 

. . . 

. 

<- 


E X P E RIM  E N T A L 


15 


According  to  the  methods  given  by  Mr.  Westermann  the 
work  was  taken  up.  The  esterification  was  made  by  using  the  p- 
nitro  “benzoyl  chloride  with  the  alcohol,  then  the  nitro  ester  was 
reduced  by  using  powdered  iron  with  a little  hydrochloric  acid. 

For  the  higher  esters  he  could  not  get  sufficient  amounts  to  have 
a large  excess  as  in  the  case  of  the  methyl  ester,  so  a slight  ex- 
cess only  was  used.  In  the  case  of  the  higher  esters  it  is  nec- 
essary to  use  ethyl  alcohol  as  a solvent  in  the  reduction,  in  or- 
der that  the  re-acting  substances  may  be  more  intimately  mixed  in 
the  reducing  mixture. 

PREPARATION  OF  TEE  ISOPROPHYL  ESTER. 

Forty  grams  of  the  p-nitro  benzoyl  chloride  was  put  in 
a 500  c.c.  flask  and  twenty  cubic  centimeters  of  isopropyl  alco- 
hol was  added.  The  mixture  was  heated  on  a water  bath.  At  first 
the  reaction  took  place  rapidly  giving  off  hydrochloric  acid  fumes. 
This  small  amount  of  alcohol  can  hardly  keep  the  mixture  in  solu- 
tion unless  the  water  bath  is  kept  fairly  warm,  it  was  refluxed  on 
the  bath  for  six  hours. 

The  excess  of  isopropyl  alcohol  was  distilled  off  then 
the  ester  distilled  under  diminished  pressure,  it  boiled  at  195°  - 
200°  with  15  mm.  of  pressure,  yielding  3?  grs , or  84$  yield. 


2 6. 


The  purified  ester  was  then  reduced  by  using  30  grs. 

of  p-nitro  benzoic  ester  with  160  grs.  of  powdered  iron.  The 

two  powdered  solids  were  put  in  a flask  and  shaken  long  enough 

to  he  mixed  well,  then  enough  water  and  ethyl  alcohol  were  added 

cent imeter 8 

to  make  a thin  paste.  A few  cubic/ of  hydrocloric  acid  were  added 
to  catalyze  the  process  and  it  was  stirred  for  one  hour  with  a 
mechanical  mixer  driven  by  a motor.  The  reduction  mixture  was 
allowed  to  cool  then  ether  was  added  to  extract  the  amine,  equal 
volumes  of  solid  and  ether  were  shaken  together  several  times  to 
be  sure  and  dissolve  as  much  of  amino  as  was  possible.  Then  the 
reduction  residue  was  neutralized  with  Na2  CO3  and  extracted 
twice  with  ether.  The  ether  extractions  were  filtered,  the  ether 
distilled  off  and  the  amine  a brownish  residue  remained.  This 
brownish  residue  was  dissolved  in  methyl  alcohol,  then  water  was 
added  until  the  amine  was  perc ipitated.  The  yield  was  about  95 % 
of  this  crude  ester  which  haa  the  anaesthetic  power.  It  was  not 
purified  further. 

Prepara tion  of  Secondary  Butyl  Alcohol. 

Secondary  butyl  alcohol  was  prepared  by  a modification 
6 

of  Clark’s  method  according  to  directions  given  by  Dr.  Marvel, 
Twenty-four  grams  of  magnesium  with  two  hundred  cubic  centimeters 
of  dry  ether  were  put  in  a flask  and  one  hundred  and  fifteen  grama 
of  ethyl  bromide  were  added  slowly  by  means  of  a separatory  funnel. 
After  all  the  magnesium  was  dissolved  an  sther  solution  of  freshly 


c7 
^ • 


distilled  acetyl  aldehyde  was  dropped  into  the  magnesium  reagent* 
This  reaction  was  very  violent  and  had  to  he  kept  in  an  ice  hath, 
in  order  not  to  decompose  the  acetaldehyde.  After  all  the  acet- 
aldehyde was  dropped  in,  the  mixture  was  allowed  to  stand  one-half 
hour  then  the  Greynard'a  reagent  was  decomposed  hy  pouring  slowly 
on  ice  and  hydrochloric  acid, the  ether  layers  were  dried  with 
Kg  C03  and  distilled.  Yield  about  20  grams.  This  was  much  low- 
er than  Dr.  Marvel  had  obtained. 

Preparation  of  the  Secondary  Butyl  Ester. 

The  preparation  of  the  secondary  butyl  ester  was  then 
tried.  It  was  prepared  in  the  same  way  as  the  isopropyl  ester; 
but  only  the  theoretical  amount  of  alcohol  was  used;  this  mix- 
ture could  not  be  heated  with  the  direct  flame  as  it  charred  very 
easily  driving  off  the  alcohol,  leaving  a black  mass  which  yielded 
nothingbut  p-nitro  benzoic  acid,  on  distillation.  Another  run  was 
tried  using  an  oil  bath  heated  to  about  60°  for  about  six  hours 
but  this  was  not  hot  enough  to  cause  the  reaction  to  take  place. 
The  alcohol  was  given  off  on  distillation  also  the  p-nitro  benzoyl 
chloride  and  no  reaction  had  taken  place.  Therefore,  more  heat 
must  be  applied  but  not  too  much.  Lack  of  time  prevent  further 
work  on  this  secondary  butyl  ester  of  p-nitro  benzoic  acid. 

Preparation  of  the  Para-Nitro  Benzoyl , Chloride . 

The  p-nitro  benzoyl  chloride  was  prepared  by  mixing 
finely  ground  p-nitro  benzoic  acid  and  phosphorus  pentachloride 


i- 


r 


■ 


t 

*• 

, 

t. 

, . 

. 

» 

. 

- .. 

23. 

together.  Both  substances  must  he  absolutely  dry  and  powdered 

and  the  PCL_  gradually  added  with  constant  stirring  to  the  acid, 
o 

Theoretical  amounts  were  used  after  the  violent  reaction  ceased  the 
mixture  was  heated  on  the  steam  hath  for  one  hour  then  the  ochy- 
chloride  distilled  off  and  the  p-nitro  benzoyl  chloride  distilled 
under  diminished  pressure--  good  yields  were  obtained. 


0 


- 

- • k ^ . 

' • • . - , . 


■.  ■ s 


CONCLUSION 


& . 


The  method  of  esterifying  the  para  nitro  henzohl  chloride 
with  the  alcohol  proved  very  successful  for  the  preparation  of  the 
isoprophyl  ester.  Good  yields  were  obtained , therefore , the  method 
would  be  a good  one  for  practical  work. 

The  method  of  preparing  the  p-nitro  benzoyl  chloride  by 
means  of  distillation  after  the  reaction  had  taken  place  proved  to 
be  more  successful  than  to  decompose  the  oxychloride  and  the  penta- 
chloride  by  means  of  water.  In  the  latter  method  much  of  the 
chloride  is  converted  back  to  the  acid.  Therefore,  the  para-ni- 
tro  benzoyl  chloride  was  prepared  by  using  theoretical  amounts 
of  dry  phosphorus  chloride  with  dry  powdered  para-nltro  benzoyl 
chloride.  After  the  first  violent  reaction  had  ceased  the  mixture 
was  heated  for  one  hour  on  the  steam  bath  then  the  oxychloride  was 
distilled  off  and  para-nitro  benzoyl  chloride  distilled  under 
diminished  pressure* 

The  para-nitro  ester  was  reduced  by  powdered  iron  and 
hydrochloric  acid  using  ethyl  alcohol  as  a solvent  for  the  reducing 
mixture* 

If  the  heating  is  properly  controlled  secondary  butyl 
ester  can  be  prepared  in  the  same  way  as  the  isopropyl  ester  of 
para-amino  benzoic  acid. 


30 


BIBLIOGRAPHY  PART  III 


BOOKS: 

1«  Corning  J,  Leonard 

2 . Knapp , H . 

3.  Speigel,  Leopold 
translated  by 
Leudkwig  and  Boylstar 

4.  Bielstein 

PAPERS  IN  PERIODICALS  AND  JQ1 

5.  Biggs,  Dr.  H.  M. 

6.  Clark 

7.  E inhorn  and  Seuffert 

8.  Einhorn  and  Oppenheimer 

9.  Erdman 

10.  Limpricht  and  Sarr 

11.  Borris  and  Green 

12.  Salowski 

13.  Sturmers  and  Luders 

14.  Yorlanders  and  F.  Meyer 


Local  Anaesthesia 
Appleton  and  Co. (1886) 


Cocaine  and  its  Uses 
in  Surgery. 

Putnam  Sons ,N.Y. (1885) 

Chemical  Constituents 
and  Physiological  Action 
D.Van  Nostrand  & Co. 

N.Y.  (1915) 

Bandbuch  der 
Leopold  Voss, Hamburg 
(1801) 


J . Ame r . Med.  Assoc. 

; 176 ; Ja.  17,  (1885) 

J.A.C.S.  30;  1149 

Ber.  43  2995-300  K (1910)' 

Ann. 

311;  158  (1910) 

Ber.  32; 1215  (1899) 

Ann. 

203; 278  (1899) 

Amr,  Ch.  Jor, 

26;  305 

Ber.  28;  1921  (1895)' 

Deut.  Med.  Wochschr. 

34;  2310  (1908)’ 

Ann. 

320 ; 135  (1902) 


PATENTS 


15. 

D.  R.  P. 

213459 

16. 

D.  R.  P. 

211801 

17. 

Brit.  Pat. 

4321 

(21) 

CO 

. 

D.  R.  P. 

218389 

19. 

U.S.  A.  P. 

958110 

(23)' 

• 

o 

CM 

Brit.  Pat. 

17928 

(23) 

21,  Various  Esters  of  Para  Amino  Benzoic  Acid 

Thesis  for  Bachelor  of  Science  in  Chemistry , 1920. 


The  author  wishes  to  express  her  thanks 
and  appreciation  for  the  guidance  and  assistance 
given  her  hy  Doctor  Roger  Adams  during  this  work. 


I 


\ 


